Tox and Hound – The Dirty on Dantrolene

Dantrolene is one of the few, true “muscle relaxers”. It was discovered in 1967 and approved by the FDA in 1979. Unlike paralytic neuromuscular blockers, dantrolene works post-synaptically, at the sarcoplasmic reticulum in the myocyte. It binds to the ryanodine receptor in skeletal muscle (RYR1), preventing sarcoplasmic calcium-induced calcium release.

When RYR1 works normally, calcium gets released from the sarcoplasmic reticulum and binds to troponin, exposing actin. This allows myosin to bind with actin to produce muscle contraction. When there is too much calcium, it causes excess muscle contraction. Without enough calcium, myosin is blocked from binding to actin. When dantrolene is at steady-state in healthy human volunteers, it produces a 75% reduction in muscle twitch without full paralysis. It reduces grip strength in volunteer subjects by over 50%, taking 20 hours to return to normal. Residual weakness can persist for up to 48 hours. [Flewellen 1983 PMID: 6614536]
Photo montage created by Raul654 (wikipedia.org)

Malignant hyperthermia (MH) is a hypermetabolic crisis that occurs when genetically susceptible people are exposed to inhaled anesthetics and/or depolarizing paralytics. It is associated with various muscular dystrophies and myopathies, although it mostly occurs in seemingly healthy patients. It is autosomal dominant and has variable penetrance. After exposure, the carefully controlled process of calcium release in the muscle goes haywire, causing uncontrolled calcium release and subsequent muscle contraction. The leading theory is that triggering agents cause an abnormal RYR1 to stay open for a prolonged period of time, although there are multiple genetic abnormalities associated with malignant hyperthermia, so there may be more than one mechanism. Increased muscular activity leads to excessive heat generation causing hyperthermia, rhabdomyolysis, acidosis, and hyperkalemia. Given the underlying common etiology, dantrolene is the perfect antidote for MH.

By sbharris (wikipedia.org)

MH previously had a mortality of 70-80% that dropped to 10% after dantrolene became available [Krause 2014 PMID: 15023018]. It is given as a 2.5 mg/kg bolus, repeated every 15 minutes until symptoms are under control. There are three different formulations of dantrolene available today: Dantrium™, Revonto™, and Ryanodex™. Dantrium™ and Revonto™ are similar in that they both come in 20 mg vials that are reconstituted using 60 mL of normal saline. Each vial also contains a hefty 3 grams of mannitol. A single 2.5 mg/kg dose of dantrolene for an 80 kg patient would require 10 vials per dose, with a total of 30 grams of mannitol per dose. A dose of mannitol to treat elevated intracranial pressure for the same patient is 20 grams. That’s a lot of shaking and a lot of sugar. In contrast, Ryanodex™ contains 250 mg of dantrolene per vial and 125 mg of mannitol per vial. Each vial requires 5 mL of normal saline for reconstitution.

One of the major downsides of dantrolene is its risk of hepatotoxicity. While the risks are low, cases of irreversible, and sometimes fatal, hepatotoxicity have occurred. The risk of hepatotoxicity is more common in women and patients over the age of 35.

Dantrolene also carries a risk of tissue necrosis with extravasation. Other effects include weakness, respiratory failure, confusion, ptosis and bulbar palsy. Dantrolene is used as an oral therapy for chronic spasticity. It was found to be as effective as benzodiazepines for the treatment of spasticity, but the benefit of dantrolene is that it didn’t cause as much drowsiness and discoordination as diazepam [Pinder 1977 PMID: 318989]. Dantrolene is now considered a second-line agent for the treatment of spasticity due to its hepatotoxic side effects. [Chang 2013 PMID: 25750484]

The use of a RYR1 antagonist as a treatment for conditions of RYR1 dysfunction makes perfect sense. Because people often conflate one hyperthermic patient for another, dantrolene has been suggested as a therapy for other hyperthermic conditions, such as serotonin syndrome, neuroleptic malignant syndrome, and heat stroke. Is there a role for dantrolene outside of malignant hyperthermia?

The use of dantrolene in hyperthermia associated with MDMA is more controversial. Hyperthermia and death associated with MDMA has been reported in the literature since 1987 [Dowling 1987 PMID: 2881002; Brown 1987 PMID: 2886672; Smilkstein 1987 PMID: 2884326]. The initial mechanism of MDMA-associated hyperthermia was unknown, and because it shares some clinical features with MH (e.g., hyperthermia, rhabdomyolysis, agitation), it was thought that it might be related to underlying ryanodine receptor dysfunction. This led to multiple reports of the efficacy of the use of dantrolene [Hall 2006 PMID:16595612; Moon 2007 PMID: 17573404; Mallick 1997 PMID: 9315942]. A review of 71 cases of MDMA-associated hyperthermia reported improved survival with dantrolene administration [Grunau 2010 PMID: 20880437]. However, this review is limited by the lack of comparative data on the benefit of benzos, paralytics and cooling, in addition to the ever present problem of publication bias. While there is initial animal data in swine (who are a natural model of malignant hyperthermia) that suggests a link between MH and MDMA-associated hyperthermia [Fiege 2003 PMID: 14576550], later studies showed that MDMA induced hyperthermia regardless of genetic susceptibility to MH. [Shutte 2013 PMID: 23138574; Gerbershagen 2012 PMID: 22089516]. MDMA-associated hyperthermia is also more complex than MH. It involves catecholamine release [Sprague 2005 PMID: 15942349], mitochondrial dysfunction [Rusyniak 2005 PMID: 15644431], increased motor activity, and increased susceptibility to ambient heat [Zaretsky 2014 PMID: 24765530]. Given the complex mechanisms by which MDMA can cause hyperthermia, what is the role of a ryanodine antagonist in a clinical syndrome that has no clear link to ryanodine dysfunction? Are patients responding to dantrolene because it’s a ryanodine receptor antagonist, or are they responding because dantrolene is acting as a general muscle relaxer? If this is the case, would benzodiazepines, or even paralysis for severe cases, be just as effective as dantrolene without the added risk of hepatotoxicity? What about the role of active cooling? Is aggressive cooling better than any pharmaceutical intervention? Active cooling in combination with pharmaceutical intervention? Bueller?

Neuroleptic malignant syndrome (NMS) is a rare idiopathic syndrome that can occur with the chronic administration of dopamine antagonists or the sudden withdrawal from dopamine agonists. This leads to abnormal thermoregulation that causes hyperthermia, muscle rigidity, rhabdomyolysis. NMS has a high mortality when it’s untreated. NMS can be treated using bromocriptine, a dopamine agonist (Editor note: Whether it is effective is for another post…). Dantrolene has been reported to be beneficial in NMS [Perry 2012 PMID: 22563571; Berman 2011 PMID: 23983836; Tsutsumi 1998 PMID: 9766694; Addonizio 1987 PMID: 2886157], although it’s use in NMS remains controversial [Adnet 2000 PMID: 10928001; Reulbach 2007 PMID: 17222339]. The reported successful use of dantrolene for NMS is associated with therapy lasting days [Berman 2011 PMID: 23983836] verses the minutes-hours that it takes for dantrolene to treat malignant hyperthermia. The timing of therapy suggests its effect on muscular relaxation more than its effect on ryanodine dysfunction. If this is the case, then the literature on spasticity suggests that there may be more efficacious and safer therapies for muscular relaxation.

Heat stroke is another hyperthermic condition that can occurs due to exposure to high environmental temperatures. It can also develop during periods of exertion in a hot, humid environment. There is both human [Roux-Buisson 2016 PMID: 26994242] and animal [Michelucci 2017 PMID: 28465322] data that suggests some relationship between heat stroke and patients with ryanodine receptor mutations; although a majority of heat stroke is thought to be due to environmental exposure. Studies regarding the use of dantrolene for the treatment of heat stroke are varied. It it shown to increase the effectiveness of cooling measures without affecting outcomes, so at this time, there is no indication for the use of dantrolene in the setting of heat stroke [Handad 2005 PMID: 15693989].

Dantrolene has been proposed as a potential therapy in other hyperthermic disease states, including thyroid storm [Christensen 1987 PMID: 3567006], MAOI toxicity [Verrilli 1987 PMID: 3574693; Kaplan 1986 PMID: 3944965], and baclofen withdrawal [Khorasani 1995 PMID: 7726408]. All of these present with hyperthermia and increased motor tone. If there’s any question of malignant hyperthermia as a potential cause of a patient’s presentation, they should receive dantrolene as quickly as possible. However, if the underlying mechanism for hyperthermia is not caused by ryanodine receptor dysfunction, then is dantrolene the best treatment? In a perfect evidence-based medicine world, we would have randomized-controlled trials comparing dantrolene to benzodiazpines to paralytics to cooling, and in all the various combinations, for all the various hyperthemic diseases. As it stands today, there is not enough data to support the use of dantrolene in hyperthermic states that are not associated with ryanodine receptor dysfunction. It is safer to use benzodiazepines to help control agitation and hyperactivity, and external cooling to treat hyperthermia. Critically ill patients may even require neuromuscular blockade in cases of severe agitation and hyperactivity.

[…] The Dirty on Dantrolene, a true muscle relaxer. Many likely have never used this medication in practice, but it’s use in emergency medicine should not be overlooked or forgotten. Here is just a taste of the post: […]